A R l t P tiA Regulatory Perspective on Biotechnology Product Comparability P t l O th C ti b tProtocols: On the Continuum between Traditional and Enhanced Approaches

Patrick Swann, Deputy DirectorDivision of Monoclonal AntibodiesOffice of Biotechnology Products

OPS, CDER

CMC Strategy ForumCMC Strategy ForumPractical Use of Expanded Change Protocols

January 28, 2013

Disclaimers

The views and opinions expressed should not be used in place of

regulations, published FDA guidances or discussions with the Agency.

Outline of Today’s Presentation• Summarize statute regulations and• Summarize statute, regulations, and

guidance relevant to comparability protocols• Summarize DMA experience withSummarize DMA experience with

comparability protocols highlighting the evolution of approaches

• Summarize OBP pilot program experience with expanded change protocols (eCP)

• Discuss examples of analytical capability which can support eCPsDi ibl f t li ti f• Discuss possible future applications of protocols

FD&C Act Chapter V: Drugs and DevicesDrugs and Devices

• “ a drug made with a major manufacturing• …a drug made with a major manufacturing change may be distributed only if, before the distribution of the drug as so made the holderdistribution of the drug as so made, the holder involved submits to the Secretary a supplemental application for such change andsupplemental application for such change and the Secretary approves the application.”

FD&C Act Chapter V: Drugs and DevicesDrugs and Devices

• “ a major manufacturing change is a• …a major manufacturing change is a manufacturing change that is determined by the Secretary to have substantial potential toSecretary to have substantial potential to adversely affect the identity, strength, quality, purity or potency of the drug as they may relatepurity, or potency of the drug as they may relate to the safety or effectiveness of a drug.”

Changes to an approved application

S ti 601 12( ) ll f th f• Section..601.12(e) allows for the use of protocols “…describing the specific tests

d t di d t it i t band studies and acceptance criteria to be achieved to demonstrate the lack of d ff t f ifi d t fadverse effect for specified types of

manufacturing changes...”• “Any such protocols, or change to a

protocol, shall be submitted as a supplement requiring approval from FDA prior to distribution…”

Draft Guidance:Benefits of a CPBenefits of a CP

• “The use of a comparability protocol could allow an applicant to implement CMC changes and place a product in distribution sooner than without use of a comparability protocol.”

Draft Guidance:Draft Guidance:Changes inappropriate to a CP

• Nonspecific plans for CMC changes• Changes for which the adverse effectChanges for which the adverse effect

cannot be evaluated by studies, tests, etc• Changes that warrant submission of a new• Changes that warrant submission of a new

INDCh th t i S/E li i l• Changes that require S/E, nonclinical, PK/PD data

Draft Guidance:Basic Elements of a CPBasic Elements of a CP

• Description of planned change(s)p p g ( )• Tests and Studies to be completed• Analytical Procedures to be used• Analytical Procedures to be used• Acceptance Criteria• Proposed reporting category

mAb Approvals (cumulative) &mAb Approvals (cumulative) & Comparability Protocols

50

40

45

50

30

35

er

15

20

25

Num

b CumulativeApproved

CompProtocols

5

10

Protocols

0

</= 1995 1996 - 2000 2001 - 2005 2006 - 2010 2011 - 2012Calendar Year

CMC Supplements andCMC Supplements and Comparability Protocols

400

300

350

200

250

300

mbe

r

150

200

Num Supplements

Received

CompP t l

50

100 Protocols

0

</= 1995 1996 - 2000 2001 - 2005 2006 - 2010 2011 - 2012Calendar Year

mAb CPs have been submitted formAb CPs have been submitted for what purpose?

20

12

14

16

18

20

4

6

8

10 Before2006

After2005

0

2

tion/A

rea

d/or S

cale

ctFa

cility

Method

(s)

Facili

ty/Bldg

/Loca

tio

uring

Proces

s and

/o

uct to

Mult

i-Prod

uct

Analyt

ical M

e

Fa

Manufac

tur

Single

Produc

Offi f Bi t h l P d t (OBP) Pil tOffice of Biotechnology Products (OBP) Pilot Program (FR notice 2008)

• In many cases, Comparability Protocols have been used for a single manufacturinghave been used for a single manufacturing change.P t l b d lit b d i• Protocols based on quality-by-design submissions will focus on critical quality tt ib t l t d t h i t f l tiattributes related to chemistry, formulation,

and process design.

Office of Biotechnology Products (OBP) Pilot Program (FR notice 2008)

• Such protocols will be referred to as Expanded Change Protocols. Expanded p g pChange Protocols will describe the quality-by-design, risk based approach linking y g , pp gattributes and processes to product performance, safety, and efficacy.p , y, y

ICH Q11Manufacturing Process Development

Enhanced

• Systematic approach toSystematic approach to evaluation and understanding

• Functional relationships that link material attributes and process parameters to CQAs

Traditional• Identify Potential

CQA’s• Define

M f t i

process parameters to CQAs• Use of QRM to establish an appropriate control strategy which can include proposals for d i ( )Manufacturing

Process• Define Control

Strategy

design space(s)

16Slide courtesy of Betsy Fritschel, J&J

Sample ECP Q&A

• Does the Agency agree that the strategy and outlined content proposed for the ECP are appropriate to support implementation of future process changes to the [drug name] drug substance manufacturing process ?substance manufacturing process…?

• While the intent ECP is to allow for more expanded changes your proposal to includeexpanded changes, your proposal to include undefined and significant process improvement changes is not supported by the product and c a ges s o suppo ed by e p oduc a dprocess knowledge conveyed to the Agency.

Sample eCP comments• A general principle as described in ICH• A general principle as described in ICH

Q5e is that the comparability assessment is related to the manufacturing change.is related to the manufacturing change. Specifically:– “To identify the impact of a manufacturing y p g

process change, a careful evaluation of all foreseeable consequences for the product should be performed ”should be performed.

Expanded Analytical Capability to Support eCPto Support eCP

• Improved/newer methods to better pcharacterize / control some “foreseeable consequences”consequences– Identify methods sensitive to change

Gl l ti fil th d i t– Glycosylation profile method improvements– SVP: moving beyond <788>– Demonstrating stability profile equivalence

Consider Sensitivity of Methods toConsider Sensitivity of Methods to Distinguish Differences*

• pH• Concentration (A280)

• 2nd derivative near-UV• Far-UV CD

• SEC• CEX

IEF

• FT-IR• Near-UV CD

I t i i fl• cIEF• SDS-PAGE• cSDS

• Intrinsic fluorescence• Extrinsic fluorescence• Dynamic light scattercSDS

• Potency• Peptide Mapping

Dynamic light scatter• SEC-MALS-QELS• Differential scanning p pp g g

calorimetry

*Maity et al, Curr. Pharm. Biotech. 2012*Change in mAb filling procedures. See Maity et al, Curr. Pharm. Biotech. 2012

Consider Sensitivity of Methods toConsider Sensitivity of Methods to Distinguish Differences*

• pH• Concentration (A280)

• 2nd derivative near-UV• Far-UV CD

• SEC• CEX

IEF

• FT-IR• Near-UV CD

I t i i fl• cIEF• SDS-PAGE• cSDS

• Intrinsic fluorescence• Extrinsic fluorescence• Dynamic light scattercSDS

• Potency• Peptide Mapping

Dynamic light scatter• SEC-MALS-QELS• Differential scanning p pp g g

calorimetry

*Change in mAb filling procedures. See Maity et al, Curr. Pharm. Biotech. 2012

Impact of Filling Pump on Particulates

“The results indicate that the rolling diaphragmThe results indicate that the rolling diaphragmPump, peristaltic pump, and time-pressure Filler generated notably less protein sub-visibleparticles than the rotary piston pump.”

Nayak et al, J. Pharm Sci., Vol 100, 4198-42042011

Improved Glycosylation Analytical Methods

Strategies for the profilingStrategies for the profiling, characterisation and detailed structural analysis of N-linked OligosaccharidesTharmalingam et al.Glycoconjugate JournalAugust 2012

The separation of human IgG N-glycans b HPLC ( ) d UPLC (b) UPLCby HPLC (a) and UPLC (b). UPLC can baseline resolve 24 peaks in the IgG glycan pool.

ICH Q5e – Role of Stability Data inICH Q5e – Role of Stability Data in Comparability

• When considering the comparability of products, the manufacturer should evaluate, for example:– The need for stability data, including those

t d f l t d tgenerated from accelerated or stress conditions, to provide insight into potential product differences in the degradation p gpathways of the product and, hence, potential differences in product-related substances and product related impurities;product-related impurities;

Demonstrating stability profile equivalence

Plots of hx and new process slopes with EAC

From Sidor et al, BioPharm International, March 2011

ICH Q11 Example 2: Risk Ranking of Process Parameters

• A quality risk assessment utilising prior knowledge and development studies can be used to rank process parameters based on theirused to rank process parameters based on their relative potential to have an effect on product quality if parameter ranges were changed.q y p g g

• The ranking of parameters from the quality risk assessment can be used to communicate with regulators regarding a lifecycle management approach to assure continual improvementapproach to assure continual improvement throughout the product lifecycle.

ICH Q11 example 2: Risk Ranking of Process Parameters

• Initial FilingThe histogram shows the potential impact to quality forfuture changes to parameter ranges based on theknowledge and understanding at the time ofsubmission.submission.

• Lifecycle Management Options for extension of rangesranges – Design Space– Proposal for management of changesp g g– Managed by PQS without prior regulatory approval

Lower Risk Higher Risk

Extension of ranges would normally initiate a regulatory post-approval change process

The applicant can include in the original submission a proposal for extension of ranges for these parametersp

Extension of ranges is addressed primarily via the PQS (Q10)

Manufacturing Changes &Manufacturing Changes & Process Validation

• “A description of the planned change a well• A description of the planned change, a well-justified rationale for the change, an implementation plan, and quality unit approval p p q y ppbefore implementation must be documented (§211.100). Depending on how the proposed change might affect product quality additionalchange might affect product quality, additional process design and process qualification activities could be warranted. Certain manufacturing changes may call for formal notification to the Agency before implementation, as directed by existing regulations ”as directed by existing regulations…

Summary & Conclusions• Comparability protocols have a long history of

successful implementation and have been applied to facility changes, process changes andapplied to facility changes, process changes and method changes.

• Expanded change protocols have been discussed and implemented under OBP’s QbDdiscussed and implemented under OBP s QbD Pilot program

• Enhanced understanding derived from utilization gof targeted and up-to-date analytical capabilities can facilitate comparability protocols

• Comparability protocols can be part of long term• Comparability protocols can be part of long term product lifecycle management strategy

Acknowledgements

• OBP, DMA colleagues for helpful comments

• Authors of recent papers (see next slide)• Betsy Fritschel (PhRMA topic lead for• Betsy Fritschel (PhRMA topic lead for

Q11) for arrow graphic

References1. Sidor, L., Burdick, R., Cowley, D., Kendrick, B., “Demonstrating y g

comparability of stability profiles using statistical equivalence testing”, BioPharm International, March 2011, 36-42.

2. Nayak, A., Golandene, J., Bradford, V., Perkins, M., “Characterization of subvisible particle formation during the fillingCharacterization of subvisible particle formation during the filling pump operation of a monoclonal antibody solution”, J. Pharm Sci., 2011, 100, 4198-4204.

3. Maity, H., Lai, Y., Srivastava, A., Goldstein, J. “Principles and Applications of selective biophysical methods for characterizationApplications of selective biophysical methods for characterization and comparability assessment of a monoclonal antibody”, Curr. Pharm. Biotech., 2012, 13, 2078-2101.

4. Tharmalingam, T., Adamczyk, B., Doherty, M.A., Royle, L., Rudd, P M “Strategies for the profiling characterisation and detailedP.M., Strategies for the profiling, characterisation and detailed structural analysis of N-linked oligosaccharides”, Gycoconj. J. pubilished online 26 August 2012.

5. Federici, M., Lubiniecki, A., Manikwar, P., Volkin, D.B., “Analytical l l d f l d h i i bililessons learned from selected therapeutic protein comparability studies”, Biologicals, 2012, 1-17.